Plexiform neurofibromas (PNs) are some of the most disfiguring and therapeutically challenging lesions that dermatologists confront. PNs are mostly associated with autosomal dominant neurofibromatosis type 1. Rarely, they may also be seen in germline p16 mutation-positive heritable melanoma and Cowden syndrome. Diffuse PNs of the face and neck rarely appear after the age of 1, and rarely develop on other parts of the body after adolescence. In contrast, deep nodular PNs often originate from spinal nerve roots and usually become symptomatic in adulthood. PNs have an 8% to 12% chance of changing into a malignant peripheral nerve-sheath tumor. Continuous pain in the tumor, rapid tumor growth, hardening of the tumor, or weakness or numbness in an arm or leg with a plexiform neurofibroma suggests malignant transformation (1).
According to Avery et al, “Neurofibromatosis type 1 is caused by a mutation in the NF1 tumor-suppressor gene on chromosome 17q11.2-350 kb, 60 exons. The gene product neurofibromin (2818 amino acids) contains a domain with significant homology to Ras GTPase-activating proteins and thus regulates Ras activity. Lack of functional neurofibromin leads to dysregulated Ras signaling and tumorigenesis. Plexiform neurofibromas are composed of neoplastic Schwann cells, fibroblasts, perineural cells, and mast cells. Neoplastic Schwann cells lack NF1 gene expression, and loss of neurofibromin is associated with elevated levels of activated Ras. Activated Ras results in the initiation of a cascade of signaling events, such as activation of Raf and mitogen-activated protein kinase, that lead to increased cell proliferation. In addition, activation of the mammalian target of rapamycin pathway has been identified in benign and malignant NF1 tumors, and the tumor microenvironment contributes to the pathogenesis of PN. Schwann cells have been shown to secrete kit ligand, which recruits mast cells and results in abnormal growth. Additional cooperating events, such as increased expression of growth factors and growth factor receptors, including endothelial growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor, may contribute to PN development and progression. Many of the potential treatment targets for PNs are shared with cancers, such as Ras, cKIT, angiogenesis, and mammalian target of rapamycin” (2).
Dombi et al conducted a phase 1 trial of selumetinib, an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable PN to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). The authors also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of PN) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the PN. A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included an acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. In conclusion, the data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects (3).
In reviewing this article, I reached several conclusions: 1) selumetinib clearly decreases the size of PN as demonstrated in panel B of figure 1; 2) ongoing therapy must be maintained for a beneficial effect; 3) long-term studies are required to determine if resistance to selumetinib develops, and if so, how to circumvent it; 4) perhaps greater efficacy could occur by combining selumetinib with agents directed to other receptors and growth factors involved in the pathogenesis of PN; 5) therapy, be it surgical, medical, or a combination of the two, still requires a multidisciplinary approach between geneticists, dermatologists, ophthalmologists, plastic surgeons, and neuro-oncologists; and 6) we are on the cusp of targeted therapy to improve the lives of these patients who, until recently, could only pray for such advances.
- Bakshi SS. Plexiform neurofibroma. Cleve Clin J Med 2016; 83: 792.
- Avery RA, et al. Orbital/periorbital plexiform neurofibromas in children with neurofibromatosis type I: Multidisciplinary recommendations for care. Ophthalmology 2017; 124: 123=32.
- Dombi E, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromatosis. N Engl J Med 2016; 375: 2550-60.
*the image is from Staser K, et al. Mast cells and the neurofibroma microenvironment. Blood 2010; 116: 157-64.